Oxazole n-amidino-carboxyamides with natriuretic action

ABSTRACT

The invention relates to the synthesis and the pharmacological activity, particularly the natriuretic activity, of novel acylguanidine compounds. The new compounds are of the formula   WHEREIN N REPRESENTS THE NUMBERS 0, 1 OR 2.

United States Patent [72] lnventor Enzo Marchetti [56] References CitedRome OTHER REFERENCES P 794788 Theilheimer- Synthetic Methods of OrganicChemistry" [221 F'led 1969 Vol 9 186 No 439-Interscience 1955 45Patented Nov. 23, 1971 [73] Assignee Instituto Farmacologico SeronoS.p.A. Primary Emmi'Ie'A|eX Male Rom Ital Assistant Examiner-R. V. Rush[32] Priority Jan. 31, 1968 Attorney-Ostrolenk, Faber, Gerb & Sofi'en[33] Italy [31] 12243 A/68 I ABSTRACT: The invention relates to thesynthesis and the pharmacological activity, particularly the natriureticactivity, [54] OXAZOLE N-AMIDINMARBQXYAMID WITH of novel acyl-guanidinecompounds. The new compounds are NATRIURE'I'IC ACTION of the formula 4Claims, No Drawings 06H 52 us. Cl 260/307 R, i

424/272 anal (CH2)n C ONHCNH [51] m. C] com 85/44 0 #11 [50] Field ofSearch 260/307 wherein n represents the numbers 0, l or 2.

NH 05115 H:

I B]. (I) R =NH- -NH2 B S 2)n' 0 =OH I) R =allto y (Ia), (Ila), (IIIa)m=0 (Ib), (11b), (lllb) m=1 The novel N-amidinocarboxyamides of thepresent invention are endowed by themselves with poor diureticproperties, however, when administered to test animals together withknown diuretic products as chlorotiazide, dihydrochlorotiazide,acetazole-amide, furosemide, etc., the carboxyamides greatly strengthenthe diuretic and natriuretic activity thereof, while significantlydepressing the removal of potassium ions.

Particularly in the rat, the simultaneous per os administration of 20mgJkg. hydrochlorotiazide and I00 mg./kg. of N- amidino-carboxyamide(la) causes a removal of water and sodium ions nearly double incomparison with animals treated with only the same dosage ofhydrochlorotiazide, while the concentration of potassium ions in theurine of animals treated with the above cited association issubstantially of the same order as the urine of untreated controlanimals.

A particular property of the novel guanidine derivatives (I) is the verypoor acute toxicity thereof (in the order of 2000-3000 mgJkg. per os" inthe rat and mouse, respectively).

The phannacological properties of N-amidino-carboxyamides (1) allowsutilization in association with substances of high diuretic activity inhuman therapy, while removing or compensating the undesirable, excessiveexcretion of potasium ions which is generally caused by theadministration of a number of diuretic agents.

The above-mentioned associations may be, in particular, useful in thetreatment of afflictions deriving from an increase or decrease of theconcentration of electrolytes in the organism, in arterioushypertension, as well as in all of the pathological afi'lictions of theoedema type.

Acyl-guanidines or N-amidino-carboxyamides (I) have been preparedaccording to known processes, such as the action of guanidine onsuitable esters of the acids (ll) (either in the presence or in theabsence of a suitable solvent), or by converting said acids to thecorresponding chlorides (for instance through the action of thionylchloride); said acyl chlorides have been reacted (without previousisolation) with guanidine itself in a suitable solvent (dioxane,dimethylsulfoxide).

The esters of the acids (II) have been obtained by reacting desylaminehydrochloride with (methyl or ethyl) monoester monochlorides of suitabledicarboxylic acids, particularly of oxalic, malonic, succinic acids; theso obtained corresponding substituted amides (IV), upon warming withcondensing agents in a suitable solvent (benzene, xylene) afford theesters (lll Among the above-mentioned intermediates only the ester Illa,R=OC,H and the amide (IVa, R=C,I-l,) have been already described in theliterature.

Alkaline hydrolysis of esters (lllb) and (lllc) has allowed thecorresponding acids (Ilb, and (Ilc) to be prepared, however, in the caseof esters (Illa), hydrolysis results in the simultaneous opening of theheterocyclic ring and does not allow the acid (Ila) to be obtained.

The following examples illustrate briefly the methods employed forsynthesizing acyl-guanidines (I).

EXAMPLE 1 One mole desylamine hydrochloride (or free base) is suspended(or dissolved) in a suitable anhydrous solvent (for instance benzene,toluene, xylene, etc.) and the suspension under stirring is warmed with1 mole of an alkoxy-oxalylchloride, an alkoxy-malonylchloride or analkoxy-succinylchloride, respectively, while prosecuting heating untilHCI release ends.

The reaction may be carried out also by starting with desylaminehydrochloride or free base; in the presence of a substance of a basicnature (i.e. triethylamine, pyridine, etc.) which is capable of blockingthe acidity which develops in the reaction.

Upon the reaction completion, crystallization of the amides (IV) isobtained by cooling, for example: N(methoxalyl)- desylamine (lVa,R=Cl-l;,; m.p. 158 C.), N-(ethoxymalonyl)- desylamine (IVb, R=C,H m.p.89-90 C.), N-(methoxysuccinyl)-desylamine (lVc; R=CH,; m.p. l03-l04 C.).

Cyclization of the amides (IV) to the corresponding esters of4,5-diphenyl-2-oxazoly|-carboxylic, -acetic and -3- propionic acids,respectively, is attained by the action of -bomethoxy-oxazole (Illa,R=Cl-l,; m.p. 1 18 C.); 4,5-diphenylphosphorus oxychloride, in the warm,in suitable anhydrous solvents (i.e. benzene, toluene, xylene), or byutilizing the condensation agent itself as the solvent means.

The esters (III) are obtained from the reaction mixture by removing thesolvent, treating with icewater, extracting with a suitable solvent(ether, chloroform, etc.) and crystallizing from an appropriate solvent(i.e. diluted ethyl alcohol) the residue obtained by extraction solventevaporation. For example the following esters are obtained:4,5-diphenyl2-car- 2-carbethoxymethyl-oxazone (Illb, R=C,H,,; m.p. 6769C. 4,5-diphenyl-2( Z-carbomethoxy-ethyl)-oxazole (lllc, R=CH m.p. 58-59C.).

The esters (III) in solution in a suitable solvent (i.e. methanol,dioxane, etc.) are reacted with guanidinc base (from 2 to 5 moles) attemperatures in the range from 20 to C.; upon reaction completion theproduct precipitation is completed by dilution with water, whereafterthe acylguanidines are filtered, washed with water and then crystallizedfrom an appropriate solvent (dimethylformamide, dimethylsulfoxide,diluted alcohol, etc.). N-amidino-carboxya'mides of4,5-diphenyl-2-oxazolyl-carboxylic (la, m.p. 245-247 C.), -acetic (lb,m.p. 202 C.), -3-propionic acids (Ic, m.p. l60 C.) are so obtained.

EXAMPLE 2 The esters (lllb) and (lllc) are saponified by treating themwith alkaline hydroxides in a hydroalcoholic solution, at a temperaturecomprised between 20 and 80 C.; by acidification and subsequentcrystallization from diluted alcohol, 4,5- diphenyl-2-oxazolyl-aceticacid (Ilb, m.p. l l78 C.) and (4,5-diphenyl-2-oxazolyl)-3-propionic acid(llc, m.p. l60-l6 1 C. are obtained respectively.

Acyl chlorides which are obtained from said acids by treatment with SClallow N-amidino-carboxyamides (I) to be prepared by subsequent reactionwith guanidine.

The embodiments of the invention in which an exclusive privilege orproperty is claimed are defined as follows:

1. An oxazole N-zimidino-carboxyamide of the formula

2. The compound of claim 1, wherein said carboxyamide is the N-amidino-carboxyamide of 4,5-diphenyl-2-oxazolylcarboxylic acid.
 3. The compound of claim 1, wherein said carboxyamide is the N-amidino-carboxyamide of 4,5-diphenyl-2-oxazolyl-acetic acid.
 4. The compound of claim 1, wherein said carboxyamide is the N-amidino-carboxyamide of (4,5-diphenyl-2-oxazolyl) -3-propionic acid. 